AXL/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma

Zuo, Qiang; Liu, Jing; Huang, Liping; Qin, Yifei; Hawley, Teresa S.; Seo, Claire; Merlino, Glenn; Yu, Yanlin

doi:10.1038/s41388-018-0205-4

Cited by 85 publications

(82 citation statements)

References 48 publications

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“…The role of RBMX protein in inhibiting the PI3K/AKT pathway in melanoma, especially the functional inability of a frameshift variant S303 of RBMX to exert this function, needs a further investigation. Downregulation of AKT activity could be connected with loss of AXL in 11_TRAR and 12_PLXR cell lines, as positive regulation between AXL and AKT has been reported [95]. An elevated level of SOX10 protein in resistant cell lines derived from DMBC21 cells might contribute to enhanced activation of AKT [96].…”

Section: Discussionmentioning

confidence: 91%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resistance to vemurafenib or trametinib to provide insight into resistance mechanisms. Dissecting the mechanisms accompanying the development of resistance, we have shown that (i) most of genetic and non-genetic alterations are triggered in a cell line-and/or drug-specific manner; (ii) several changes previously assigned to the development of resistance are induced as the immediate response to the extent measurable at the bulk levels; (iii) reprogramming observed in cross-resistance experiments and growth factor-dependence restricted by the drug presence indicate that phenotypic plasticity of melanoma cells largely contributes to the sustained resistance. Whole-exome sequencing revealed novel genetic alterations, including a frameshift variant of RBMX found exclusively in phospho-AKT high resistant cell lines. There was no similar pattern of phenotypic alterations among eleven resistant cell lines, including expression/activity of crucial regulators, such as MITF, AXL, SOX, and NGFR, which suggests that patient-to-patient variability is richer and more nuanced than previously described. This diversity should be considered during the development of new strategies to circumvent the acquired resistance to targeted therapies.

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Section: Discussionmentioning

confidence: 91%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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“…In melanoma with BRAF mutation, AXL overexpression has been reported to attenuate the sensitivity to inhibitors of BRAF/MEK, and cooperative antitumor effects with AXL inhibition were indicated in vitro and in vivo 35,36 . Indeed, a clinical trial evaluating the efficacy of R428 combined with the MEK inhibitor trametinib and BRAF inhibitor dabrafenib is already underway (NCT02872259).…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of the inhibitors of RAF/MEK and AXL on KRAS‐mutated ovarian cancer cells with high AXL expression

et al. 2020

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KRAS mutation is frequently seen in a subtype of ovarian cancer categorized as type 1. The KRAS‐MAPK pathway, which is closely involved in type 1 cancer progression, is under the regulation of receptor tyrosine kinases (RTKs). AXL, one of the RTKs, has been reported to be overexpressed in ovarian cancer and contributes to the poor prognosis. However, there is no useful target‐based agent against such gene profiles. We examined the combined effect of the dual RAF/MEK inhibitor CH5126766 and AXL inhibitor R428 on the growth of ovarian cancer HEY‐T30 and OVCAR‐5 cell lines, both of which bear KRAS mutation and express AXL at a high level, using the WST‐8 assay and the colony formation assay. The synergistic effect of the combination was evaluated by the combination index. The apoptotic cells were analyzed by flow cytometry. The expression of apoptotic proteins and the phosphorylation of MAPK and AKT pathway proteins were investigated by western blotting. We found that CH5126766 and R428 suppressed the phosphorylation of ERK and AKT, respectively, and their combination synergistically inhibited the growth of both cell lines with enhancement of apoptosis accompanied by the Bim upregulation. Combined treatment with CH5126766 and R428 is expected as the novel therapeutic option for KRAS‐mutated ovarian cancer with high expression of AXL.

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“…Inhibition of the PI3K-AKT pathway can occur upon AXL perturbation (23,43,44). In the absence of AKT, there is less ERBB3 ubiquitination for degradation by Nrdp1, a situation that can result in increased ERBB3 protein levels and phosphorylation (32).…”

Section: Discussionmentioning

confidence: 99%

Cross-Talk between Receptor Tyrosine Kinases AXL and ERBB3 Regulates Invadopodia Formation in Melanoma Cells

2019

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The invasive phenotype of metastatic cancer cells is accompanied by the formation of actin-rich invadopodia, which adhere to the extracellular matrix and degrade it. In this study, we explored the role of the tyrosine kinome in the formation of invadopodia in metastatic melanoma cells. Using a microscopy-based siRNA screen, we identified a series of regulators, the knockdown of which either suppresses (e.g., TYK2, IGFR1, ERBB3, TYRO3, FES, ALK, PTK7) or enhances (e.g., ABL2, AXL, CSK) invadopodia formation and function. Notably, the receptor tyrosine kinase AXL displayed a dual regulatory function, where both depletion or overexpression enhanced invadopodia formation and activity. This apparent contradiction was attributed to the capacity of AXL to directly stimulate invadopodia, yet its suppression upregulates the ERBB3 signaling pathway, which can also activate core invadopodia regulators and enhance invadopodia function. Bioinformatic analysis of multiple melanoma cell lines points to an inverse expression pattern of AXL and ERBB3. High expression of AXL in melanoma cells is associated with high expression of invadopodia components and an invasive phenotype. These results provide new insights into the complexity of metastasis-promoting mechanisms and suggest that targeting of multiple invadopodia signaling networks may serve as a potential anti-invasion therapy in melanoma.Significance: These findings uncover a unique interplay between AXL and ERBB3 in invadopodia regulation that points to the need for combined therapy in order to prevent invadopodia-mediated metastasis in melanoma.

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AXL/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma

Cited by 85 publications

References 48 publications

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Synergistic effect of the inhibitors of RAF/MEK and AXL on KRAS‐mutated ovarian cancer cells with high AXL expression

Cross-Talk between Receptor Tyrosine Kinases AXL and ERBB3 Regulates Invadopodia Formation in Melanoma Cells

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